Cartilage gene linked to bone cancers

Changes to cartilage linked to bone cancer offers a possible new diagnostic approach

For the first time, researchers from The Wellcome Trust Sanger Institute, the Royal National Orthopaedic Hospital and
UCL Cancer Institute, have linked a gene central to the production of cartilage, COL2A1, to the development of
a common type of bone cancer. Their discovery may act as an important way to diagnose this type of cancer in the
future, improving patient care.

The team also uncovered the Indian Hedgehog pathway that contributes to the development of this bone cancer in one in
five patients with the disease. Drugs that inhibit this pathway already exist, and therefore the team's finding offers
potential new treatment options for many patients with this cancer type.

Chondrosarcoma is a cancer of cartilage and is the second most common type of primary bone cancer. The main treatment
option is surgery as chemotherapy or traditional radiotherapy provides no significant benefit for patients with this
disease. This study offers new approaches to diagnosing this tumour and possible new treatments.

The team screened the functioning regions of the genome in 49 patients with chondrosarcoma. They found that mutations
in the gene COL2A1 played a role in cancer development in almost 40 per cent of the patients.

COL2A1 is the gene for a type of collagen. Collagens are fibrous proteins that are responsible for the tensile
strength of bone, cartilage and other tissues. This collagen is particularly important for the development of cartilage
and thus the gene is very active in cartilage cells. This is the first time that a collagen gene has been shown to be
involved in the development of a cancer. The team speculates that the high activity of COL2A1 in cartilage
cells could contribute to the formation of mutations that underlie the development of chondrosarcoma.

" We've looked at the entire genetic landscape of this bone cancer in patients, revealing the importance of
thoroughly characterising all cancer types and subtypes in developing better therapeutic and diagnostic strategies.
"

Dr Patrick Tarpey

The team looked at the activity of COL2A1 in other bone cancers but did not find mutations. The high frequency
of mutation in COL2A1 in chondrosarcoma patients could therefore become a diagnostic marker to differentiate
it from other bone cancers.

The team also identified two biological pathways, IHH and RB1 that contributes to the development of chondrosarcoma in
many patients. Drugs that target the IHH pathway are already used to treat other cancer types. These drugs could be
good candidate treatments for patients with chondrosarcoma.

"Our study has brought us a step closer to understanding fully the biological mechanisms that
underlie this bone cancer," says Dr Andy Futreal, senior author and honorary WTSI faculty member now at MD
Anderson. "This is significant progress that hopefully will lead to more effective approaches to
treat this disease."

"Our research would not have been possible without the help of the patients who donated their
samples," says Professor Adrienne Flanagan, lead author from the Royal National Orthopaedic Hospital NHS Trust
and UCL. "We hope the ongoing scientific and clinical research being conducted will help improve
the outlook for those currently suffering at the hands of this disease."

Notes to Editors

Publication details

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma.

RNOH

RNOH is the largest specialist orthopaedic hospital in the UK and is regarded as a leader in the field of orthopaedics.

The Trust provides a comprehensive and unique range of neuro-musculoskeletal healthcare, ranging from acute spinal
injuries to orthopaedic medicine and specialist rehabilitation for chronic back pain sufferers.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

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The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.